In my previous studies, performed in the Jackson Aging Center at the Jackson Laboratory, we used mouse models with a focus on understanding the genetics, physiology and pathology of aging, as well as identifying genetic loci and genes that regulate aging and healthspan. In these studies, we characterized the aging phenotypes of different inbred strains and identified that development traits, such as circulating IGF1 and age of female sexual maturation, are significantly correlated with longevity across the mouse strains. We further verified this correlation by showing that depressing IGF1 by a natural allele could delay female sexual maturation and extend longevity. Using the genetic and bioinformatic methods, we identified a potential aging gene, nuclear receptor interacting protein 1 (Nrip1). We found that the Nrip1 knockout females have a significantly lower level of circulating IGF1 and delayed age of sexual maturation compared with wild-type controls. Other groups have reported that depressing Nrip1 could significantly reduce fat tissue, increase insulin sensitivity and enhance resistance to high-fat diet-induced obesity and diabetes. I am applying the K01 award to support my career development, from identifying candidate genes for aging to investigating the underlying mechanisms. In this study, I will: Aim 1.Characterize the effects of NRIP1 deficiency on metabolism traits and IGF1 signaling in aging. We will test if the protective effects of knocking out Nrip1 could persist through aging. Aim 2. Test the hypothesis that depressing Nrip1 expression in white fat tissue would improve metabolism during aging. Nrip1 null mice are retarded in growth and impaired in female reproduction. To identify a therapeutic target, we will test whether knocking out Nrip1 in white fat tissue would improve metabolism. The tissue-specific knockout of Nrip1 will also provide a valuable model to further understand the role of Nrip1 in the regulations of metabolism and aging. Aim 3. Test the hypothesis that global and white fat tissue-specific reduction of Nrip1 expression would extend longevity. We will compare longevities of Nrip1 null and white fat-specific knockout mice to wild-type controls. To investigat the interaction between Nrip1 and diet restriction, we also will compare longevities for these two mutants to wild-type controls under diet restriction. Nrip1 has wide and complicated effects on regulating metabolisms that relate to many biological mechanisms, including insulin sensitivity, growth hormone/IGF1 signaling, inflammation, mitochondrial function and oxidative stress. These mechanisms have also been suggested as critical to regulating aging. In this project, we propose to use a combination of techniques to study these mechanisms. Thus, if the proposal is awarded, I will not only learn many new research techniques that will significantly enhance my research skills, but I will also study many important aging-related biological mechanisms that are important for building my knowledge of the genetic network of regulating aging. It will also give me a chance to explore the potential therapeutic targets for translational medicine. Importantly, as I continue to build on the solid foundation of genetic aging research from my previous studies, this award will significantly contribute to my long-term goals of revealing the genetic network and molecular mechanisms that regulate aging, as well as identifying novel therapeutic targets for interventions of translational medicine that extend healthspan. To ensure the success of my career development, we have assembled a team of experts in the areas that are proposed to be studied in this proposal. My mentor (Prof. A. Bartke), co-mentor (Prof. H. Van Remmen) and consultants/collaborators (N. Barzilai, J. Kopchick, M. Adamo, M. Parker) have considerable experience in writing and evaluating grant proposals, as well as in researching diverse areas of mammalian endocrinology, metabolism, intracellular signaling and molecular biology pertinent to the biology of aging. We have also developed a complete plan for enhancing my research skills and pushing my career forward, including communicating with my mentor, co-mentor and consultants, training in critical techniques, attending conferences, writing papers and applying new research grants, as well as mentoring younger researchers.